Familial medullary carcinoma of the thyroid (MCT) is a tumor of the calcitonin-producing C-cells of the thyroid gland, caused by a fully penetrant, autosomal dominant gene. It occurs as a solitary disease and also as part of the multiple endocrine neoplasia 2 syndrome. MCT is of fundamental medical and biological importance because it is one of the clearest examples of genetically determined cancer. Delineation of the mechanism of action of the MCT gene may therefore provide important insights into basic genetic mechanisms of carcinogenesis. At the present time, both the product and location of the MCT gene are unknown. This study will combine the resources of 3 large well-studied MCT kindreds, in whom appropriate individuals have undergone biochemical testing for early, presymptomatic MCT phenotype assignment, and a collection of more than 500 polymorphic DNA probes covering most of the human genome. With these clinical data and DNA samples already in hand, and the growing DNA probe collection at its current size, the probability of detecting linkage in the first 16 months of the investigation is 80% at LOD greater than 3 and 91% at LOD greater than 2. When linkage is detected, the chromosomal location of the MCT gene will be determined and a targeted approach will be taken to map closely linked DNA markers that flank the gene locus. This will narrow the region containing the gene to within a few million base pairs, establish a high resolution genetic map of the region, and provide a set of highly informative diagnostic markers that can be used to test for the MCT gene at an early age before the disease is phenotypically expressed. This will permit definitive treatment of affected individuals and reassurance to unaffected individuals at risk for inheriting the disease. This set of closely linked DNA markers will also permit physical mapping of the MCT locus, which will eventually lead to identification and characterization of the MCT gene itself. With this information in hand, it will be possible to explore the biological mechanism that causes MCT and provide a model for the genetic determination of human cancer.